Urinary incontinence is a common but very severe condition which mostly causes patients to be embarrassed, encounter difficulties, and be driven to despair. Clearly, there is a strong demand for a reliable and safe method of treating urinary incontinence. To date such a demand has not been satisfied to an appropriate level.
Urinary incontinence refers to a condition in which urine involuntarily flows out during the storage phase, and which is caused when there is a functional or organic abnormality in one or both of the urinary bladder and the urethra. Urinary incontinence occurs when bladder smooth muscle is involuntarily contracted so that the internal pressure of the urinary bladder is increased, or when urethral closure pressure created by the urethral sphincter and a supporting tissue surrounding the urethra is too weak to repel the internal pressure of the normal urinary bladder. Urinary incontinence is divided into several types depending on the pathology. Broad types are: urge incontinence; reflex incontinence; overflow incontinence (poorly compliant bladder), stress incontinence, total incontinence; and nocturnal enuresis.
Urge incontinence is a condition in which urine involuntarily flows out accompanying a strong urge to urinate, or after feeling an urge to urinate, a patient cannot resist urine outflow and wets before reaching a toilet. These are divided into motor and sensory types. Motor urge incontinence is caused by a disorder of an inhibitory pathway for the micturition reflex, or excitation of an exitatory pathway, a representative example of which is neurogenic bladder due to a lesion, such as for example a cerebrovascular disorder and a brain tumor. Representative examples of sensory urge incontinence include cystitis and urethritis.
Reflex incontinence is a condition in which when the urinary bladder is filled with urine to some extent without a normal urge to urinate, the urinary bladder is reflectively contracted, so that urine involuntarily flows out. Reflex incontinence includes neurogenic bladder due to injury of the spinal cord above the urination center in the sacral spinal cord, urinary incontinence of infants, and the like.
Overflow incontinence is a condition in which since urine cannot be sufficiently excreted, the urinary bladder is excessively filled with urine and the urine gradually flows out. Overflow incontinence includes neurogenic bladder (poorly compliant bladder) due to injury of peripheral nerves, and disorders of the passage of the lower urinary tract due to prostatic hypertrophy or cancer.
Stress incontinence is a symptom in which when a patient strains in sneezing or coughing, laughs, runs, or the like, so that abdominal pressure is rapidly increased, urine flows out without contraction of the urinary bladder. The increase in the abdominal pressure leads to a raise in the internal pressure of the urinary bladder. In this case, if the increased internal pressure exceeds the urethral closure pressure, urine flows out. Females more often suffer from this disorder. A major cause of stress incontinence is that supporting tissues surrounding the urethra are seriously weakened by parturition or aging, so that urethral closure pressure cannot be sufficiently generated.
Total incontinence is a condition characterized by dysfunction of the urethral sphincter, and in which urine flows out from the urethra at all times irrespective of the presence or absence of abdominal pressure. The cause of total incontinence is injury of the urethral sphincter caused by trauma of the pelvis or surgery of the prostate.
Nocturnal enuresis is also called bed-wetting, which is a condition in which patients of 4 or more years old, which is the age at which the habit of urinating is established, unconsciously void urine during sleep though they do not have an organic abnormality in the urinary tract or the nerve system and can urinate normally (no urinary incontinence) on awakening. This disorder is caused by the premature inhibitory mechanism of the central nerve system for the micturition reflex.
At present, anticholinergic agents are generally used for treatment of the following patients having urine storage disorders: (1) neurogenic bladder patients who have urinary incontinence due to the hyperactivity of urinary bladder and involuntarily urinate; (2) neurogenic bladder patients who do not have abnormal urinary bladder contraction but have a poorly compliant urinary bladder in which the internal pressure of the urinary bladder gradually increased as urine is filled; (3) one subset of patients who chiefly complain of pollakiuria; etc. Clinically, despite the efficacy of anticholinergic agents against urine storage disorders, when the anticholinergic agents are actually used, urinary bladder contraction is inhibited in urination so that urination disorders are often exacerbated to cause side effects, such as increased residual urine and anuresis.
As described above, clearly, urinary incontinence is one of today's major diseases, but current therapeutic methods are not satisfactory. There is a demand for a novel drug for treating urinary incontinence. The term “urination disorder” as used herein refers to an abnormal urination condition, such as urinary incontinence, caused by insufficient extension of bladder smooth muscle. Examples of urination disorders include urinary incontinence (e.g., urge incontinence), frequent urination, nocturnal pollakiuria. An agent capable of promoting extension of bladder smooth muscle would be expected to help bladder smooth muscle extend during storage phase to reduce the internal pressure of the urinary bladder. Thus, such an agent would be considered to be useful as drugs for treatment of urinary incontinence and other symptoms relating to urination.
It has been known that adrenomedullin has a vasodilatory action. For example, Nakamura et al., Jpn. J. Pharmacol. 67, 259-262 (1995) has reported in FIG. 1 that contracted mesenteric artery is extended by addition of adrenomedullin in a concentration-dependent manner. However, vasodilation cannot be considered to be identical with passive extension of muscle of the urinary bladder. For example, Nishimura et al., British J. Pharmacology, 120, 193-200 (1997) describes in FIG. 6 that addition of adrenomedullin to the urinary bladder does not cause contraction or extension (active extension) of the urinary bladder.
The present invention is intended to solve the above-described problems. The objective of the present invention is to provide a novel agent for promoting passive extension of bladder smooth muscle.